Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

ABSTRACT

A process for preparing compounds of the formula ##STR1## wherein R and R 2  are independently --OH, --O(lower alkyl) or --0-benzyl and the remaining variables are as defined in the specification, comprising 
     (a) treating with a strong base in an anhydrous organic solvent a lactone of the formula ##STR2##  respectively, wherein Ar 10  is Ar 1  or a suitably protected hydroxy- or amino-substituted aryl, and R&#39; and R 2&#39;  are R and R 2  as defined above or are suitably protected hydroxy groups; 
     (b) reacting a product of step (a) with an imine of the formula ##STR3##  wherein Ar 20  and Ar 30  are Ar 2  or Ar 3  or suitably protected hydroxy- or amino-substituted aryl; 
     c) quenching the reaction with an acid; and 
     d) removing protecting groups as necssary.

This application is a continuation-in-part of U.S. Ser. No. 102,440,filed Sep. 21, 1993 abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to hydroxy-substituted azetidinones usefulas hypocholesterolemic agents in the treatment and prevention ofatherosclerosis, and to the combination of a hydroxy-substitutedazetidinone of this invention and a cholesterol biosynthesis inhibitorfor the treatment and prevention of atherosclerosis. The invention alsorelates to a process for preparing hydroxy-substituted azetidinones.

Atherosclerotic coronary heart disease (CHD) represents the major causefor death and cardiovascular morbidity in the western world. Riskfactors for atherosclerotic coronary heart disease include hypertension,diabetes mellitus, family history, male gender, cigarette smoke andserum cholesterol. A total cholesterol level in excess of 225-250 mg/dlis associated with significant elevation of risk of CHD.

Cholesteryl esters are a major component of atherosclerotic lesions andthe major storage form of cholesterol in arterial wall cells. Formationof cholesteryl esters is also a key step in the intestinal absorption ofdietary cholesterol. Thus, inhibition of cholesteryl ester formation andreduction of serum cholesterol is likely to inhibit the progression ofatherosclerotic lesion formation, decrease the accumulation ofcholesteryl esters in the arterial wall, and block the intestinalabsorption of dietary cholesterol.

A few azetidinones have been reported as being useful in loweringcholesterol and/or in inhibiting the formation of cholesterol-containinglesions in mammalian arterial walls. U.S. Pat. No. 4,983,597 disclosesN-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram, et al.,in Indian J, Chem., Sect. B, 29B, 12 (1990), p. 1134-7, disclose ethyl4-(2-oxoazetidin-4-yl)phenoxy-alkanoates as hypolipidemic agents.European Patent Publication 264,231 discloses1-substituted-4-phenyl-3-(2-oxo-alkylidene)-2-azetidinones as bloodplatelet aggregation inhibitors. European Patent 199,630 and EuropeanPatent Application 337,549 disclose elastase inhibitory substitutedazetidinones said to be useful in treating inflammatory conditionsresulting in tissue destruction which are associated with variousdisease states, e.g. atherosclerosis.

WO93/02048, published Feb. 4, 1993, discloses substituted β-lactamsuseful as hypocholesterolemic agents.

The regulation of whole-body cholesterol homeostasis in humans andanimals involves the regulation of dietary cholesterol and modulation ofcholesterol biosynthesis, bile acid biosynthesis and the catabolism ofthe cholesterol-containing plasma lipoproteins. The liver is the majororgan responsible for cholesterol biosynthesis and catabolism and forthis reason, it is a prime determinant of plasma cholesterol levels. Theliver is the site of synthesis and secretion of very low densitylipoproteins (VLDL) which are subsequently metabolized to low densitylipoproteins (LDL) in the circulation. LDL are the predominantcholesterol-carrying lipoproteins in the plasma and an increase in theirconcentration is correlated with increased atherosclerosis.

When intestinal cholesterol absorption is reduced, by whatever means,less cholesterol is delivered to the liver. The consequence of thisaction is decreased hepatic lipoprotein (VLDL) production and anincrease in the hepatic clearance of plasma cholesterol, mostly as LDL.Thus, the net effect of inhibiting intestinal cholesterol absorption isa decrease in plasma cholesterol levels.

The inhibition of cholesterol biosynthesis by 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown tobe an effective way to reduce plasma cholesterol (Witzum, Circulation,80, 5 (1989), p. 1101-1114) and reduce atherosclerosis. Combinationtherapy of an HMG CoA reductase inhibitor and a bile acid sequestranthas been demonstrated to be more effective in human hyperlipidemicpatients than either agent in monotherapy (Illingworth, Drugs, 36(Suppl. 3) (1988), p. 63-71).

SUMMARY OF THE INVENTION

Novel hypocholesterolemic compounds of the present invention arerepresented by the formula I ##STR4## or a pharmaceutically acceptablesalt thereof, wherein:

Ar¹ and Ar² are independently selected from the group consisting of aryland R⁴ -substituted aryl;

Ar³ is aryl or R⁵ -substituted aryl;

X, Y and Z are independently selected from the group consisting of --CH₂--, --CH(lower alkyl)- and --C(dilower alkyl)-;

R and R² are independently selected from the group consisting of --OR⁶,--O(CO)R⁶, --O(CO)OR⁹ and --O(CO)NR⁶ R⁷ ;

R¹ and R³ are independently selected from the group consisting ofhydrogen, lower alkyl and aryl;

q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4;provided that at least one of q and r is 1, and the sum of m, n, p, qand r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1,the sum of m, q and n is 1, 2, 3, 4 or 5;

R⁴ is 1-5 substituents independently selected from the group consistingof lower alkyl, --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)₁₋₅ OR⁶,--O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸,--NR⁶ SO₂ R⁹, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)₀₋₂ R⁹,--O(CH₂)₁₋₁₀ --COOR⁶, --O(CH₂)₁₋₁₀ CONR⁶ R⁷, -(lower alkylene)COOR⁶,--CH═CH--COOR⁶, --CF₃, --CN, --NO₂ and halogen;

R⁵ is 1-5 substituents independently selected from the group consistingof --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)₁₋₅ OR⁶, --O(CO)NR⁶ R⁷, --NR⁶R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸, --NR⁶ SO₂ R⁹,--COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)₀₋₂ R⁹, --O(CH₂)₁₋₁₀--COOR⁶, --O(CH₂)₁₋₁₀ CONR⁶ R⁷, -(lower alkylene)COOR⁶ and--CH═CH--COOR⁶ ;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

R⁴ is preferably 1-3 independently selected substituents, and R⁵ ispreferably 1-3 independently selected substituents. Preferred arecompounds of formula I wherein Ar¹ is phenyl or R⁴ -substituted phenyl,especially (4-R⁴)-substituted phenyl. Ar² is preferably phenyl or R⁴-substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar³ ispreferably R⁵ -substituted phenyl, especially (4-R⁵)-substituted phenyl.When Ar¹ is (4-R⁴)-substituted phenyl, R⁴ is preferably a halogen. WhenAr² and Ar³ are R⁴ - and R⁵ -substituted phenyl, respectively, R⁴ ispreferably halogen or --OR⁶ and R⁵ is preferably --OR⁶, wherein R⁶ islower alkyl or hydrogen. Especially preferred are compounds wherein eachof Ar¹ and Ar² is 4-fluorophenyl and Ar³ is 4-hydroxyphenyl or4-methoxyphenyl.

X, Y and Z are each preferably --CH₂ --. R¹ and R³ are each preferablyhydrogen. R and R² are preferably --OR⁶ wherein R⁶ is hydrogen, or agroup readily metabolizable to a hydroxyl (such as --O(CO)R⁶, --O(CO)OR⁹and --O(CO)NR⁶ R⁷, defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.Preferred are compounds wherein m, n and r are each zero, q is 1 and pis 2. Also preferred are compounds wherein p, q and n are each zero, ris 1 and m is 2 or 3. More preferred are compounds wherein m, n and rare each zero, q is 1, p is 2, Z is --CH₂ -- and R is --OR⁶, especiallywhen R⁶ is hydrogen. Also more preferred are compounds wherein p, q andn are each zero, r is 1, m is 2, X is --CH₂ -- and R² is --OR⁶,especially when R⁶ is hydrogen.

Another group of preferred compounds is that wherein Ar¹ is phenyl or R⁴-substituted phenyl, Ar² is phenyl or R⁴ -substituted phenyl and Ar³ isR⁵ -substituted phenyl. Also preferred are compounds wherein Ar¹ isphenyl or R⁴ -substituted phenyl, Ar² is phenyl or R⁴ -substitutedphenyl, Ar³ is R⁵ -substituted phenyl, and the sum of m, n, p, q and ris 2, 3 or 4, more especially 3. More preferred are compounds whereinAr¹ is phenyl or R⁴ -substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl, Ar³ is R⁵ -substituted phenyl, and wherein m, n andr are each zero, q is 1 and p is 2, or wherein p, q and n are each zero,r is 1 and m is 2 or 3.

This invention also relates to a method of lowering the serumcholesterol level in a mammal in need of such treatment comprisingadministering an effective amount of a compound of formula I . That is,the use of a compound of the present invention as an hypocholesterolemicagent is also claimed.

In still another aspect, the present invention relates to apharmaceutical composition comprising a serum cholesterol-loweringeffective amount of a compound of formula I in a pharmaceuticallyacceptable carrier.

The present invention also relates to a method of reducing plasmacholesterol levels, and to a method of treating or preventingatherosclerosis, comprising administering to a mammal in need of suchtreatment an effective amount of a combination of a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I and acholesterol biosynthesis inhibitor. That is, the present inventionrelates to the use of a hydroxy-substituted azetidinone cholesterolabsorption inhibitor of formula I for combined use with a cholesterolbiosynthesis inhibitor (and, similarly, use of a cholesterolbiosynthesis inhibitor for combined use with a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I) to treat orprevent atherosclerosis or to reduce plasma cholesterol levels.

In yet another aspect, the invention relates to a pharmaceuticalcomposition comprising an effective amount of a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I, a cholesterolbiosynthesis inhibitor, and a pharmaceutically acceptable carrier. In afinal aspect, the invention relates to a kit comprising in one containeran effective amount of a hydroxy-substituted azetidinone cholesterolabsorption inhibitor of formula I in a pharmaceutically acceptablecarrier, and in a separate container, an effective amount of acholesterol biosynthesis inhibitor in a pharmaceutically acceptablecarrier.

In yet another aspect, the invention relates to a process for preparingcertain compounds of formula I comprising the steps:

(a) treating with a strong base a lactone of the formula ##STR5##wherein R' and R^(2') are R and R², respectively, or are suitablyprotected hydroxy groups; Ar¹⁰ is Ar¹, a suitably protectedhydroxy-substituted aryl or a suitably protected amino-substituted aryl;and the remaining variables are as defined above, provided that inlactone of formula B, when n and r are each zero, p is 1-4;

(b) reacting the product of step (a) with an imine of the formula##STR6## wherein Ar²⁰ is Ar², a suitably protected hydroxy-substitutedaryl or a suitably protected amino-substituted aryl; and Ar³⁰ is Ar³, asuitably protected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl;

c) quenching the reaction with an acid;

d) optionally removing the protecting groups from R', R^(2'), Ar¹⁰, Ar²⁰and Ar³⁰, when present; and

e) optionally functionalizing hydroxy or amino substituents at R, R²,Ar¹, Ar² and Ar³.

Using the lactones shown above, compounds of formula IA and IB areobtained as follows: ##STR7## wherein the variables are as definedabove; and ##STR8## wherein the variables are as defined above.

DETAILED DESCRIPTION

As used herein, the term "lower alkyl" means straight or branched alkylchains of 1 to 6 carbon atoms.

"Aryl" means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

"Halogeno" refers to fluorine, chlorine, bromine or iodine atoms.

The above statement, wherein R⁶, R⁷ and R⁸ are said to be independentlyselected from a group of substituents, means that R⁶, R⁷ and R⁸ areindependently selected, but also that where an R⁶, R⁷ or R⁸ variableoccurs more than once in a molecule, those occurrences are independentlyselected (e.g., if R is --OR⁶ wherein R⁶ is hydrogen, R⁴ can be --OR⁶wherein R⁶ is lower alkyl).

Compounds of the invention have at least one asymmetric carbon atom andtherefore all isomers, including enantiomers and diastereomers arecontemplated as being part of this invention. The invention includes dand l isomers in both pure form and in admixture, including racemicmixtures. Isomers can be prepared using conventional techniques, eitherby reacting chiral starting materials or by separating isomers of acompound of formula I. Isomers may also include geometric isomers, e.g.when a double bond is present. All such geometric isomers arecontemplated for this invention.

Those skilled in the art will appreciate that for some compounds offormula I, one isomer will show greater pharmacological activity thananother isomer.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase form for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxy alkylamines,N-methylglucamine and the like.

Cholesterol biosynthesis inhibitors for use in the combination of thepresent invention include HMG CoA reductase inhibitors such aslovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoAsynthetase inhibitors, for example L-659,699((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other cholesterol biosynthesis inhibitors such asDMP-565. Preferred HMG CoA reductase inhibitors are lovastatin,pravastatin and simvastatin.

Compounds of formula I can be prepared by known methods, for examplethose described below and in WO93/02048.

Method A: ##STR9## Compounds of formula Ia and Ib, wherein Ar¹, Ar²,Ar³, X, Y, Z, R, R¹, R², R³, m, n, p, q and r are as defined above, canbe prepared by treatment of an ester of formula III, wherein R¹⁰ islower alkyl such as ethyl or a chiral moiety such as menthyl or10-(diisopropylsulfonamido)isobomyl, and the remaining variables are asdefined above, with a strong base such as lithium diisopropylamide (LDA)in a suitable solvent such as tetrahydro-furan (THF) at -78° C. Asolubilizing agent such as hexamethylphosphoric triamide (HMPA) mayoptionally be added as a cosolvent. An imine of formula II, wherein Ar²⁰and Ar³⁰ are as defined above, is added, the reaction mixture is eitherwarmed to room temperature or maintained at a suitable low temperaturesuch as -78° C. for the appropriate time, followed by quenching with asuitable acid such as 1 N HCl. The product is isolated usingconventional purification techniques. When a protecting group as definedin Table 1 (below) is present on one or more of the optionally protectedgroups, an additional step comprising removal of the protecting group byconventional techniques is needed. However, for compounds of formula Ia,Ib, or any compound of formula I wherein a protected hydroxy group Ar¹⁰,Ar²⁰, Ar³⁰, R' or R^(2') is an alkoxy or benzyloxy group, such aprotecting group need not be removed to obtain a compound of formula I.When a chiral ester of formula III is used, the resulting compound offormula Ia or Ib is not racemic.

Imines of formula II (Ar³⁰ --CH═N--Ar²⁰) can be prepared from aldehydesof the formula Ar³⁰ --CHO and amines of the formula Ar²⁰ --NH₂ byprocedures well known in the art. Aldehydes of formula Ar³⁰ --CHO andamines of formula Ar²⁰ --NH₂ are commercially available or can beprepared via known procedures.

Method A: ##STR10## Compounds of formula Ic and Id, wherein thevariables are as defined above, can be prepared by a process comprisingthe following steps:

(a) Treat a lactone of formula IV, wherein the variables are as definedabove, with a strong base such as an alkyllithium (e.g.,n-butyl-lithium), a metal hydride (e.g., sodium hydride), a metalalkoxide (e.g., sodium methoxide), a metal halide (e.g., TiCI₄), metalexchange of the lithium enolate with a metal halide (e.g., zincchloride), metal exchange of the lithium enolate with a metal alkyl(e.g., 9-borabicyclononyi triflate), or, preferably, a metalamide (e.g.,LDA), in a suitable anhydrous organic solvent such as dry THF, ether orbenzene, in a dry, inert atmosphere, e.g., under nitrogen. The reactionis carried out at about 0° to about -85° C., preferably about -78° C.,over a period of about 5 to about 60 minutes, preferably about 30minutes. 1-50% of solubilizing cosolvents may optionally be added,preferably about 10% HMPA.

(b) Add an imine of formula II, wherein Ar²⁰ and Ar³⁰ are as definedabove, to the product of step (a) over a period of 5 to 60 minutes,preferably 30 minutes, maintaining the reaction mixture at about 0° toabout -85° C., preferably about -78° C., for 1 to 12 hours, preferablyabout 3 hours, or warming the reaction mixture over that time period ata rate of about 10° C. per hour to about 70° C. per hour, preferablyabout 30° C. per hour, to a temperature of about 20° C.

(c) Quench the reaction with a suitable acid such as HCl (1 N).

(d) The protecting groups on R', R^(2'), Ar¹⁰, Ar²⁰ and Ar³⁰, whenpresent, are removed, if desired, by methods well known in the art, forexample silyl protecting groups are removed by treatment with fluoride.

e) Compounds of formula I wherein any of R and R², when present, are OR⁶wherein R⁶ is hydrogen, can be converted by well known methods to othercompounds of formula I wherein R and R² are functionalized, i.e., areindependently selected from the group consisting of OR^(6a), --O(CO)R⁶,--O(CO)OR⁹ and --O(CO)NR⁶ R⁷, wherein R⁶, R⁷ and R⁹ are as defined aboveand R^(6a) is lower alkyl, aryl, or aryl-lower alkyl. For example,treatment of the alcohol with an alkyl halide in the presence of asuitable base such as NaH will afford alkoxy-substituted compounds(i.e., R or R² is OR⁶, wherein R⁶ is lower alkyl); treatment of thealcohol with an acylating agent such as acetylchloride will result incompounds wherein R or R² is --OC(O)R⁶ ; treatment of the alcohol withphosgene followed by an alcohol of the formula HOR⁹ affords compoundssubstituted with a --OC(O)OR⁹ group; and treatment of the alcohol withphosgene followed by an amine of the formula HNR⁶ R⁷ affords compoundswherein R or R² is --OC(O)NR⁶ R⁷. Compounds of formula I wherein any ofAr¹, Ar² or Ar³ has a hydroxy or amino group can be similarlyfunctionalized to obtain other compounds of formula I, i.e., wherein R⁴and R⁵ are independently --OR^(6a), --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)₁₋₅OR⁶, --O(CO)NR⁶ R⁷, --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷R⁸ or --NR⁶ SO₂ R⁹.

The product of step c, d or e is isolated using conventionalpurification techniques such as extraction, crystallization or,preferably, silica gel 60 chromatography. When a chiral lactone is used,the resulting compound of formula Ic or Id is not racemic.

Using the procedure described in steps (a)-(e), lactones of formula IVacan be used to prepare compounds of formula Ig and Ih, provided thatwhen n and r are each zero, p is 1-4: ##STR11##

Lactones of formulae IV and IVa are known in the art or can be preparedby methods well known in the art. See, for example, U.S. Pat. No.4,375,475 and J. Agric. Food Chem., 30 (5) (1982) p. 920-4.

Method B: ##STR12## Azetidinones of formula V, wherein Ar²⁰ and Ar³⁰ areas defined above, can be reacted to form compounds of formula Ie and If(i.e., compounds of formula I wherein r is 1, R² is hydroxy, and p iszero) by treatment of azetidinone V with a strong base such as lithiumisopropylcyclohexyl-amide in a suitable solvent such as THF in thepresence or absence of HMPA at -78° C., followed by the addition of analdehyde or ketone of VI, wherein Ar^(l0), X, Y, R', R¹, R³, m, n and qare as defined above. As in the case of Method A, protecting groups atAr¹⁰, Ar²⁰, Ar³⁰, R' and R^(2') are removed as necessary.

This process provides several of the possible diastereomers which can beseparated by a combination of crystallization, silica gel chromatographyand HPLC, using techniques well known in the art. The remainingdiastereomers can be obtained by inversion reactions such as theMitsunobu reaction sequence outlined below, wherein partial structuresof formula If are shown: ##STR13## In the above known process, DEAD isdiethylazodicarboxylate and PPh₃ is triphenylphosphine. The reactantsare stirred at room temperature overnight and the resultant formateester is converted to the corresponding hydroxy compound with thedesired stereochemistry.

Method C: ##STR14## Compounds of formula Ia as defined above can beprepared by reacting a chiral auxiliary such as the compound of formulaVIII with an activated carboxylic acid derivative of formula VII, forexample an acid chloride (L═Cl), a mixed anhydride formed with phenylphosphorodichloridate (L═OP(O)(Cl)OPh), an N-methyl-pyridinium esterformed from the reaction of an acid with N-methyl-2-chloropyridiniumiodide (L═2-oxy-N-methylpyridinium iodide), and a 2-thiopyridyl esterformed from the reaction of an acid chloride and 2-thiopyridine, whereinthe remaining variables are as defined above; enolizing the resultantproduct, for example with TiCl₄ and tetramethylethylenediamine (TMEDA);condensing with an aldehyde, Ar³⁰ CHO; hydrolyzing to the correspondingacid, then reacting the compound of formula IX with an amine, Ar²⁰ NH₂ ;and cyclizing the resultant compound of formula X, with, for example atrialkylphosphine and a dialkylazodicarboxylate. As in the case ofMethod A, protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R' and R^(2') areremoved as necessary. This procedure is described in detail inWO93/02048.

Method D: ##STR15## Compounds of formula Ia as defined above can also beprepared by treatment of an imine of formula II, wherein Ar²⁰ and Ar³⁰are as defined above, with an activated carboxylic acid derivative offormula VII as defined above in the presence of a tertiary amine basesuch as triethylamine, tributylamine or diethylisopropylamine in aninert solvent such as CH₂ Cl₂. Again, as in the case of Method A.protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R' and R^(2') are removed asnecessary. Use of other bases, e.g., pyridine. favors formation ofcompounds of formula Ib.

Method E: ##STR16##

In the first step, compound XII is dissolved in a suitable solvent,e.g., anhydrous CH₂ Cl₂, and treated with a Lewis acid, e.g., TiCl₄ atabout -60° C. to 0° C., preferably at about -25° C., under a dry, inertatmosphere, e.g., argon. A tertiary amine base such as TMEDA is addedand the mixture stirred at about -60° C. to 0° C., preferably at about-25° C. to -15° C., for a period of about 1 h. An imine of formula Ar³⁰CH═NAr²⁰ is added neat or optionally as a solution in a suitablesolvent, e.g. anhydrous CH₂ Cl₂, over a period of about 5 min, and thereaction is stirred vigorously at about -60° C. to 0° C., preferably atabout -25° C. to -15° C., for about 3 to 6 h, preferably about 4 h oruntil the reaction is complete by TLC. An acid, e.g. acetic acid, isadded to reaction at the reaction temperature and the mixture is allowedto warm to room temperture slowly with stirring for about 1-3 hours,preferably about 2 hours. The compound of formula XIII is isolated byextraction with a suitable solvent, e.g. CH₂ Cl₂, then purified bycrystallization or silica gel chromatography.

In the second step, the product is treated with a strongnon-nucleophilic base, such as sodium or lithium bistrimethylsilylamideat about -78° C. to 10° C. After reaction, the mixture is poured intoaqueous tartaric acid and the product isolated from the organic layer.As in the case of Method A, protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R'and R^(2') are removed as necessary. This process, including thepreparation of the starting material of formula XII, is also describedin greater detail in WO93/02048.

Method F: ##STR17## Compounds of formula Ig' and lh' (i.e., compounds offormula I wherein R is OH), wherein R^(2') is a protected hydroxy groupas defined above, and the remaining variables are as defined above, canbe prepared by reacting an imine of formula II and a carboxylic acidderivative of formula XIV, wherein the variables are as defined above,according to Method D, followed by oxidation of the resultant halide offormula XV by treatment with an oxidizing agent such as trimethylamineoxide, CrO₃ or ozone in a solvent such as DMSO. The resultant aldehydeor ketone of formula XVI is then reacted with an aryl organometallicreagent (e.g., Ar¹⁰ X_(m) MgBr, Ar¹⁰ X_(m) Li, Ar¹⁰ X_(m) MgCl or Ar¹⁰X_(m) CeCl₂) to obtain a compound of formula Ig' or Ih'. As describedabove, the Ar¹⁰, Ar²⁰, Ar³⁰ and R^(2') substituents can be converted tothe desired Ar¹, Ar², Ar³ and R² substituents by procedures well knownin the art.

Method G: ##STR18## Compounds of formula Ii having a hydroxy substituenton the side chain adjacent to the Ar¹ group (i.e., compounds of formulaI wherein m is 0) can be prepared by heating a compound of formula XVII,prepared by Method D, above, wherein the variables are as defined above,for about 1-6 hours at about 60° C. to 100° C. with a halogenating agentsuch as N-bromosuccinimide (NBS) in a suitable solvent such as CCl₄ inthe presence of an initiating agent such as benzoyl peroxide. Theresultant compound of formula XVIII, wherein Hal is Cl, Br or I and theremaining variables are as defined above, is then heated in a suitablesolvent such as CH₂ Cl₂ with a tetraalkyl-ammonium salt such as tetran-butyl-ammonium hydroxide (n-Bu₄ NOH) to obtain the compound of formulaIi. Altenatively, compound XVIII can be heated in a suitable solventsuch as CH₂ Cl₂ with tetra n-butylammonium trifluoroacetate (n-Bu₄NOC(O)CF₃) followed by treatment with a mild base such as ethanolsaturated with NH₃ to obtain compound Ii.

Method H: ##STR19##

Compounds of formula Ij (i.e., compounds of formula I wherein R is OH,R¹ is H and q is 1) are prepared from compound XIX in 2 steps. First, acompound of formula XIX, wherein the variables are as defined above, isdissolved in a suitable anhydrous solvent, e.g. THF, at about -20° C. toabout 22° C., preferably at about 0° C. under a dry inert atmosphere,e.g. argon and adding a transition metal source, e.g.tetrakis(triphenylphosphine)-palladium or palladium acetate/triphenylphosphine. An organometallic of formula Ar¹⁰ -X_(m) -Met, wherein Ar¹⁰,X and m are as defined above and Met is, for example, ZnCl or B(OH)₂, isadded to the reaction mixture at about -20° C. to about 22° C.,preferably at about 0° C., the reaction mixture is stirred for about 15min to 4 h, preferably about 1 h, and is then allowed to warm to about22° C. Addition of dilute acid, e.g. 1N HCl, followed by extraction witha suitable organic solvent, e.g. ethyl acetate (EtOAc), producescompound XX.

The ketone of formula XX is dissolved in a suitable solvent, e.g. CH₃OH, a hydrogenation catalyst is added, e.g. Pd on carbon, and themixture is exposed to H₂ gas under a pressure of about 14 psi to 100psi, preferably about 60 psi for about 1 to 24 h, preferably about 16 h.The hydrogenation catalyst is removed by filtration and the solvent isremoved in vacuo to produce a compound Ij as a mixture of alcoholdiastereomers which can be separated by conventional means.

Alternatively, a ketone of formula XX is dissolved in a suitablesolvent, e.g. THF, at about -40° C. to about 22° C., preferably at about0° C., and a suitable reducing agent such as NaBH₄, a substitutedborohydride (e.g., [cbz-proline]₃ BHNa) or a borane is added, optionallyin the presence of a suitable chiral promotor present either incatalytic or stoichiometric amounts, e.g., chiral borane of structures:##STR20## Addition of dilute acid, e.g., 1N HCl, followed by extractionwith a suitable solvent produces compounds of formula Ij. As above,protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰ and R^(2') are removed asnecessary. When either a chiral reagent or a chiral promotor is used,the resulting product is non-racemic.

Compounds of formula XIX can be prepared by a multi-step procedure asrepresented below: ##STR21## Compounds of formula XXI, wherein R¹⁰ islower alkyl and the remaining variables are as defined above, arecommercially available or can be prepared by treating the correspondingcarboxylic acid (i.e., compounds wherein the Cl is replaced by a hydroxygroup) with a chlorinating agent, e.g. SOCl₂ or oxalyl chloride, under adry atmosphere, neat or in a suitable inert organic solvent, e.g.toluene at about 40° C. to 110° C., preferably about 70° C.;alternatively, a catalyst made be added, e.g. dimethylformamide (DMF),the reaction is conducted at about 22° C. and the solvent and excessreagents are removed in vacuo. The compound XXI is reacted with a chiralauxiliary such as (S)-4-phenyl-2-oxazolidinone according to thefollowing procedure: a chiral auxiliary is treated with a strong basesuch as an alkyllithium, a metal hydride or a tertiary amine base suchas triethylamine, in a suitable anhydrous organic solvent, e.g., dryTHF, under a dry, inert atmosphere, e.g. argon, at about -85° C. to 22°C., preferably about 0° C., for about 10 min to 60 min, preferably about30 minutes. The resulting anion is reacted, without isolation, withcompound XXI in a suitable anhydrous organic solvent, e.g. dry THF,under a dry, inert atmosphere, e.g. argon, at about -85° C. to about 22°C., preferably 0° C., for about 30 min to 60 min, preferably 30 min. Thereaction is warmed to about 22° C. and continued for 1 to 12 h,preferably 6 h. Water is added and compound XXII is isolated byextraction and purified by crystallization.

The compound of formula XXII is treated in the same manner as describedin step 1 of Method E to obtain a compound XXIII.

Azetidinone ring closure can be accomplished by alternative procedures.By one method, a compound of formula XXIII is treated with a strongnon-nucleophilic base, such as sodium orlithium-bistrimethyl-silylamide, in a suitable inert organic solvent,e.g. CH₂ Cl₂, at about -78° C. to about 10° C., preferably about 0° C.The mixture is stirred for about 1 to 2 hours while gradually warming toabout 22° C. Compound XXIV is isolated by conventional extraction withCH₂ Cl₂. In another, two-step method, a compound of formula XXIII isfirst treated with mild silylating agent, e.g.N,O-bis(trimethylsilyl)acetamide at about 0° C. to about 100° C.,preferably about 40° C. for about 10 min to 60 min, preferably 30 min,then treated with a fluoride anion source, e.g. tetrabutyiammoniumfluoride (TBAF), at about 0° C. to about 100° C., preferably 40° C., andallowed to stir for about 0.5 to about 4 hours, preferably about 2hours. Compound XXIV is isolated by conventional extraction methods.

The compound of formula XXIV is hydrolysed by a suitable base, e.g.LiOH, in a suitable solvent, e.g. 66% CH₃ OH/ water at about 0° C. toabout 50° C., preferably 22° C., for about 1 to 4 hours, preferably 2hours, then extracted with a suitable solvent, e.g. EtOAc. The resultingacid is converted to the acid chloride as described above by treatmentwith a chlorination agent, e.g. oxalyl chloride, to afford compound XIX.

Method I: ##STR22##

Compounds of formula Ik, wherein Ar¹, Ar², Ar³ and R¹ are as definedabove, one of X" and Y" is --CH₂ CH₂ - and the other is selected fromthe group consisting of --CH₂ CH₂ --, --CH₂ --, --CH(lower alkyl)-,--CH(dilower alkyl) and a bond, are prepared by oxidation of an alkeneof formula XXV, wherein one of X' and Y' is --CH═CH-- and the other is--CH═CH--, --CH₂ --, --CH₂ CH₂ --, --CH(lower alkyl)-, --CH(diloweralkyl) or a bond, and the remaining variables are as defined above, canbe prepared by the following two step procedure.

A compound of formula XXV, which can be prepared by Method D, above, istreated with an oxidizing agent such as SeO₂, phenylselenic anhydride orCrO₃ in a suitable solvent such as dioxane at about 22° to 100° C. forabout 0.5 to 12 hours. After the starting material is consumed asdetermined by TLC, or 12 hours, the reaction is cooled to about 22° C.and the product XXVI is isolated by extraction.

In the second step, an allylic alcohol of formula XXVI is dissolved in asuitable solvent, e.g., EtOAc, a hydrogenation catalyst is added, e.g.,Pd on carbon, and the mixture is exposed to H₂ gas under a pressure ofabout 14 psi to 60 psi for about 1 to 12 hours. The hydrogenationcatalyst is removed in vacuo to obtain a compound of formula Ik.

Method J: ##STR23## Alcohols of formula Im and In (i.e., compounds offormula I wherein r is 1, R² is --OH, R³ is hydrogen and p is 0) can beselectively obtained from ketones of formula XXVII in three stepscomprising bromination, reduction and debromination. Since thestereochemistry of the major isomers of alcohols XXIXa and XXIXb aredifferent, one can selectively prepare either diastereomeric alcohol ingood yield.

In the above process, a ketone of formula XXVII, which can be preparedby oxidation of the corresponding hydroxy compound by well knownmethods, is halogenated, for example by treatment in an inert solvent,e.g., THF, with NaH followed by N-bromosuccinimide, to obtain a mixtureof 3-bromo-ketone compounds XXVIII (a and b). Compounds XXVIIIa andXXVIIIb are then separately reduced to the corresponding alcohols, forexample by treatment with magnesium trifiuoroacetate (Mg(TFA)₂) andt-butylamine borane (t-Bu-NH₂ -BH₃)in an inert solvent such as THF at atemperature of about -78° C. to 0° C. The resultant alcohols XXVIX aredehalogenated by treatment with tris(trimethylsilyl) silane ((TMS)₃ SiH)in a solvent such as toluene in the presence of a radical initiator suchas 2,2'-azobisisobutyronitrile (AIBN) to obtain a mixture of isomers Imand In which can be separated into individual enantiomers byconventional means, e.g., HPLC. Again, protecting groups at Ar¹⁰, Ar²⁰,Ar³⁰ and R' are removed as necessary.

Starting compounds III, V, VI, VII, VIII, XIV, XVII, XXI and XXV are alleither commercially available or well known in the art and can beprepared via known methods.

Reactive groups not involved in the above processes can be protectedduring the reactions with conventional protecting groups which can beremoved by standard procedures after the reaction. The following Table 1shows some typical protecting groups:

                  TABLE 1                                                         ______________________________________                                        Group to be                                                                            Group to be Protected and                                            Protected                                                                              Protecting Group                                                     ______________________________________                                        COOH     COOalkyl, COObenzyl, COOphenyl                                        ##STR24##                                                                              ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                           NH.sub.2                                                                                ##STR28##                                                           OH                                                                                      ##STR29##                                                                    OSi(CH.sub.3).sub.3, or OCH.sub.2 phenyl                             ______________________________________                                    

We have found that the compounds of this invention lower serum lipidlevels, in particular serum cholesterol levels. Compounds of thisinvention have been found to inhibit the intestinal absorption ofcholesterol and to significantly reduce the formation of livercholesteryl esters in animal models. Thus, compounds of this inventionare hypocholesterolemic agents by virtue of their ability to inhibit theintestinal absorption and/or esterification of cholesterol; they are,therefore, useful in the treatment and prevention of atherosclerosis inmammals; in particular in humans.

The in vivo activity of the compounds of formula I can be determined bythe following procedure:

In Vivo Assay of Hypolipidemic Agents Using the Hyperlipidemic Hamster

Hamsters are separated into groups of six and given a controlledcholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) forseven days. Diet consumption is monitored to determine dietarycholesterol exposure in the face of test compounds. The animals aredosed with the test compound once daily beginning with the initiation ofdiet. Dosing is by oral gavage of 0.2 mL of corn oil alone (controlgroup) or solution (or suspension) of test compound in corn oil. Allanimals moribund or in poor physical condition are euthanized. Afterseven days, the animals are anesthetized by intramuscular (IM) injectionof ketamine and sacrificed by decapitation. Blood is collected intovacutainer tubes containing EDTA for plasma lipid analysis and the liverexcised for tissue lipid analysis. Lipid analysis is conducted as perpublished procedures (Schnitzer-Polokoff, R., et al, Comp. Biochem.Physiol., 99A, 4 (1991 ), p. 665-670) and data is reported as percentreduction of lipid versus control.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula I and a pharmaceutically acceptablecarrier. The compounds of formula I can be administered in anyconventional dosage form, preferably an oral dosage form such as acapsule, tablet, powder, cachet, suspension or solution. Theformulations and pharmaceutical compositions can be prepared usingconventional pharmaceutically acceptable excipients and additives andconventional techniques. Such pharmaceutically acceptable excipients andadditives include non-toxic compatible fillers, binders, disintegrants,buffers, preservatives, anti-oxidants, lubricants, flavorings,thickeners, coloring agents, emulsifiers and the like.

The daily hypocholesteremic dose of a compound of formula I is about 0.1to about 30 mg/kg of body weight per day, preferably about 0.1 to about15 mg/kg. For an average body weight of 70 kg, the dosage level istherefore from about 5 mg to about 1000 mg of drug per day, given in asingle dose or 2-4 divided doses. The exact dose, however, is determinedby the attending clinician and is dependent on the potency of thecompound administered, the age, weight, condition and response of thepatient.

For the combinations of this invention wherein the hydroxy substitutedazetidinone is administered in combination with a cholesterolbiosynthesis inhibitor, the typical daily dose of the cholesterolbiosynthesis inhibitor is 0.1 to 80 mg/kg of mammalian weight per dayadministered in single or divided dosages, usually once or twice a day:for example, for HMG CoA reductase inhibitors, about 10 to about 40 mgper dose is given 1 to 2 times a day, giving a total daily dose of about10 to 80 mg per day, and for the other cholesterol biosynthesisinhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day,giving a total daily dose of about 1 mg to about 2000 mg per day. Theexact dose of any component of the combination to be administered isdetermined by the attending clinician and is dependent on the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

Where the components of a combination are administered separately, thenumber of doses of each component given per day may not necessarily bethe same, e.g. where one component may have a greater duration ofactivity, and will therefore need to be administered less frequently.

Since the present invention relates to the reduction of plasmacholesterol levels by treatment with a combination of active ingredientswherein said active ingredients may be administered separately, theinvention also relates to combining separate pharmaceutical compositionsin kit form. That is, a kit is contemplated wherein two separate unitsare combined: a cholesterol biosynthesis inhibitor pharmaceuticalcomposition and a hydroxy substituted azetidinone cholesterol absorptioninhibitor pharmaceutical composition. The kit will preferably includedirections for the administration of the separate components. The kitform is particularly advantageous when the separate components must beadministered in different dosage forms (e.g. oral and parenteral) or areadministered at different dosage intervals.

Following are examples of preparing compounds of formula I. Thestereochemistry listed is relative stereochemistry unless otherwisenoted. The terms cis and trans refer to the relative orientations at theazetidinone 3- and 4-positions unless otherwise indicated. The term "J"refers to the proton NMR coupling constant in hertz (Hz) between the3-and 4-substituted protons of the azetidinone. All NMR data is of CDCl₃solution unless otherwise indicated.

EXAMPLE 1 ##STR30##

Freshly prepare a solution of lithium diisopropylamide (LDA) bydissolving diisopropylamine (1.19 g, 11.8 mmol) in anhydrous THF (20 ml)at -78° C. under argon. Add n-butyllithium (4.9 ml, 11.8 mmol, 2.4M inhexanes) and stir for 0.5 h at -78° C. To this cold solution add,4-phenyl-butyrolactone (1.75 g, 10.8 mmol) in THF (4 ml) over 0.25 h,keeping the reaction temperature below -65° C. Stir at -78° C. for 0.25h, then add 4-methoxybenzylidine anisidine (2.33 g, 11.0 mmol) in THF (8ml) over 1 h at -78° C. Warm the reaction slowly to -50° C. over 1 h.Quench the reaction at low temperature with 1N HCl (12 ml). Partitionthe reaction mixture between ether and 1N HCl , wash the ether layerwith water, combine the ether extracts, dry over MgSO₄ and concentratein vacuo. Crystallize the crude reaction residue (3.0 g) fromEtOAc-ether to obtain 1.54 g of compound A. Reconcentrate the filtrateand chromatograph on silica gel 60, eluting with 4:1 EtOAc-hexane, andisolate additional compound A (0.385 g ) as well as compound B (0.420g).

Compound A: mp 218-220° C.; lR 1730 cm-1; CI (M+H) 374; J=5.9 Hz.

Compound B: mp 74-76° C.; lR 1730 cm-1; CI (M+H) 374; J=2.3 Hz.

Using a similar procedure and appropriate starting materials, preparecompound 1C: ##STR31##

EXAMPLE 2 ##STR32##

To a solution of compound A from Example 1 (0.5 g, 1.3 mmol) inanhydrous pyridine (2.7 ml), add acetic arthydride (0.63 ml, 6.7 mmol).Stir for 16 h, dilute with CH₂ Cl₂ and wash 3× with 1N HCl, 1× with NaCl(sat'd) and 1× with water. Concentrate the organic layer to dryness andcrystallize the residue from EtOAc to obtain the title compound (0.46g), mp 167-169° C.; lR 1745 cm-1; EI (M+)415; J=5.9 Hz.

EXAMPLE 3 ##STR33##

Freshly prepare a solution of lithium isopropylcyclo-hexylamide byadding n-butyllithium (2.84 mL of a 1.6M solution) to a solution ofisopropylcyclohexylamine (0.75 mL) in THF (100 mL) at -78° C. DissolveN-phenyl-4-(4-methoxyphenyl)-2-azetidinone (1.0 g) in THF (8 mL) andslowly add it to the reaction mixture at -78° C. After stirring for 20min, add hydrocinnamaldehyde (0.54 g) and stir the reaction mixture at-78° C. for 4 h. Quench the reaction with 10% KHSO₄ and extract theproduct with EtOAc. Separate the organic layer, wash with water and NaCl(sat'd). Concentrate the extract and purify the resultant residue on asilica gel 60 column, eluting with EtOAc:hexane (15:85) to obtain 1.15 gof product as a mixture of diastereomers. Separate the diastereomers byHPLC on a silica gel column to give three diastereomers A, B and C:

    __________________________________________________________________________       ##STR34##                                                                                                 ##STR35##                                      B                                                                                ##STR36##                                                                                                 ##STR37##                                      C                                                                                ##STR38##                                                                                                 ##STR39##                                      __________________________________________________________________________

The A, B and C diastereomers were further separated according to thefollowing reaction scheme, wherein partial structures are shown:##STR40## (The following CD spectra data [θ] are all obtained in CH₃OH.)

3D) [θ]_(227nM) =+2.0×10⁴ cm² /dM; [θ]_(241nM) =-4.6×10⁴ cm² /dM.

Elemental analysis calc for C₂₅ H₂₅ NO₃ 0.25 H₂ O: C 76.6; H 6.56; N3.57. found: C 76.66; H 6.49; N 3.64.

3E) [θ]_(227nM) =-1.95×10⁴ cm² /dm; [θ]241nM=+4.45×10⁴ cm² /dM.

Elemental analysis calc for C₂₅ H₂₅ NO₃ 0.5 H₂ O: C 75.73; H 6.61; N3.53. found: C 75.66; H 6.41; N 3.60.

3F; [θ]_(226nM) =+1.97×10⁴ cm² /dM; [θ]_(240nM) =-5.22×10⁴ cm⁴ cm² /dM.

Elemental analysis calc for C₂₅ H₂₅ NO₃ : C 77.48; H 6.51; N 3.62.found: C 77.44; H 6.53; N 3.70.

3G) [θ]_(226nM=-) 1.78×10⁴ cm² /dM; [θ]_(241nM) =+4.78×10⁴ cm² /dM (CIMS388 M⁺ H).

3H) [θ]_(226nM) =+2.24×10⁴ cm² /dM; [θ]_(241nM) =-5.4×10⁴ cm² /dM.

[α]_(D) ²⁵ =-54.4° (2.5 mg/ml CH₃ OH)

Elemental analysis calc for C₂₅ H₂₅ NO₃ : C 77.48; H 6.51; N 3.62.found: C 77.11; H 6.50; N 3.72.

3I) [θ]_(226nM) =-2.05×10⁴ cm² /dM; [θ]_(241nM) =+5.2×10⁴ cm ² /dM.(CIMS 388 M⁺ H). ##STR41##

Add DEAD (0.11 ml) to a solution of compound 3H (132 mg), PPh₃ (0.18 g)and HCO₂ H (39 ml) in THF (5 ml). Stir at room temperature overnight,then partition the reaction mixture between Et₂ O and H₂ O. Wash (brine)and dry (MgSO₄) the organic layer and concentrate to dryness. Flashchromatograph the residue using EtOAc:Hex (1:4) to obtain the formateester. Dissolve this in CH₃ OH and add 4 drops of conc. HCl. After 4 h,concentrate in vacuo and flash chromatograph the residue using EtOAc:Hex(1:3) to obtain the title compound.

[θ]224nM=+2.54×10³ cm² /dM; [θ]239nM=+5.70×10⁴ cm² /dM.

[α]_(D) ²⁰ =-157.6° (2.5 mg/ml CH₃ OH) ##STR42##

Using the procedure described for 3J, treat compound 3I to obtain thetitle compound.

[θ]222Nm=-3.4×10³ CM² /Dm; [θ]_(240NM) =-5.6×10⁴ CM² /Dm.

[α]_(d) ²⁰ =+167.2° (2.5 MG/ML ch₃ OH)

EXAMPLE 4 ##STR43##

Method 1

Step 1) To a refluxing solution of of 4-methoxybenzylidene anisidine(10.0 g, 41.5 mmol) and tributylamine (20.8 ml, 87 mmol) in toluene (100ml), add 5-bromovaleroyl chloride (8.5 g, 43 mmol) in toluene (20 ml)dropwise over 2 h. Stir the reaction mixture at 80° C. for 12 h, cool toroom temperature, wash 3× with 1 N HCl, 1× with water and dry theorganic layer over MgSO₄. Purifiy by silica gel chromatography, elutingwith ethyl acetate:hexane (4:1) to obtain 5.1 g of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-bromopropyl)-2-azetidinone (relativestereochemistry), mp 70°-73° C.; El (M⁺) 404; J=2.3 Hz.

Step 2) To a solution of the product of step 1 (5.1 g, 12.6 mmol) in(CH₃)₂ SO (20 ml), add (CH₃)₃ N(O) (2.39 g, 31.9 mmol). Heat the mixtureat 60° C. for 3 h, cool to room temperature, dilute with EtOAc, and wash3×with water. Combine the aqueous fractions and extract with EtOAc.Combine the organic fractions and concentrate. Purify the crude productby silica gel chromatography, eluting with EtOAc:hexane (1:1) to obtain1.4 g (3R, 4S)-1,4-bis-(4-methoxyphenyl)-2-oxo-3-azetidine-propanal(relative stereochemistry), an oil; EI (M⁺) 339; J =2.3 Hz.

Step 3) To a solution of the product of step 2 (0.734 g, 2.2 mmol) inTHF (4 ml) at 0° C., add phenylmagnesium bromide (2.4 ml, 2.4 mmol, 1.0Min THF) over 0.25 h. After 1 h at 0° C., add water (5 ml), separate thelayers, wash the organic layer 1× with 1 N HCl, dry with MgSO₄ andconcentrate to an oil. Purify by silica gel chromatography, eluting withEtOAc:hexane (2:1) to obtain 0.372 g of the title compound (mix ofdiastereomers) as an oil. CI (M+H) 418.

Separation of diastereomers: Apply the diastereomeric mixture from step3 to a Chiralcel OD (Chiral Technotogies Corp, PA) chromatographycolumn, eluting with hexane: ethanol (9:1) to obtain enantiomericallypure (>98%) diastereomers as follows:

    __________________________________________________________________________    4A                                                                               ##STR44##                                                                                                ##STR45##                                       4B                                                                               ##STR46##                                                                                                ##STR47##                                       4C                                                                               ##STR48##                                                                                                ##STR49##                                       4D                                                                               ##STR50##                                                                                                ##STR51##                                       __________________________________________________________________________

Method 2

Step 1) To a solution of abs(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (5.04 g,0.013 mole) in CCl₄ (20 ml) at 80° C., add NBS (2.76 g, 0.0155 mole) andbenzoyl peroxide (0.24 g, 1.0 mmole) in three equal portions over 1 h.Follow the reaction by TLC (4:1 hexane: EtOAc). Cool the reaction to 22°C., add NaHSO₄, separate the layers and wash the organic layer 3× withwater. Concentrate the organic layer to obtain the crude product.

CI (M+H) 480; ¹ H in CDCl₃ δPhC H(OH)=5.05 ppm.

Step 2) Dissolve the crude product of Step 1 in CH₂ Cl₂ (30 ml) and add40% n-BuNOC(O)CF₃ in water (30 ml). Reflux the biphasic reaction for 24h, cool, separate the layers and wash the organic layer 6× with water.Concentrate the organic layer to dryness and immediately redissolve theresidue in ethanol saturated with NH₃ (10 ml). After 1 h, concentratethe reaction mixture and partially purify by silica gel chromatography.Further purify by HPLC to obtain a 1:1 mixture of compounds 4A and 4B.The mixture can be further purified on a Chiracel OD column to obtain 4Aand 4B separately as characterized above.

Using the procedure described in Example 4, Method 2, with abs(3R,4S)-4-(4-acetoxyphenyl)-3-(3-phenylpropyl)-l-(4-methoxy-phenyl)-2-azetidinoneas the starting material, the following compounds are prepared:

    __________________________________________________________________________    4E                                                                               ##STR52##                                                                                                ##STR53##                                       4F                                                                               ##STR54##                                                                                                ##STR55##                                       __________________________________________________________________________

EXAMPLE 5 ##STR56##

To a solution of the product of step 2 of Example 4 (0.230 g, 0.68 mmol)in THF (2 ml), add the reagent derived from treatment of4-methoxymethoxy-phenyl bromide (0.159 g, 0.736 mmol) in THF (4 ml) at-78° C. with sec-butyllithium (0.6 ml, 0.78 mol, 1.3M in hexanes),followed by CeCl₃ (0.186 g, 0.75 mmol). After 4 h, extract the productand purify by chromatography in a manner similar to that described instep 3 of Example 4 to obtain 0.05 g of the title compound (mix ofdiastereomers) as an oil. CI (M+H) 478.

EXAMPLE 6 ##STR57##

Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol)in CH₂ Cl₂ (200 ml), add 4-dimethylaminopyridine (2.5 g, 0.02 mol) andtriethylamine (84.7 ml, 0.61 mol) and cool the reaction to 0 ° C. Addmethyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) as a solution in CH₂ Cl₂(375 ml) dropwise over 1 h, and allow the reaction to warm to 22° C.After 17 h, add water and H₂ SO₄ (2N, 100 ml), separate the layers, andwash the organic layer sequentially with NaOH (10%), NaCl (sat'd) andwater. Dry the organic layer over MgSO₄ and concentrate to obtain asemicrystalline product.

Step 2): To a solution of TiCl₄ (18.2 ml, 0.165 mol) in CH₂ Cl₂ (600 ml)at 0° C., add titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min,add the product of Step 1 (49.0 g, 0.17 mol) as a solution in CH₂ Cl₂(100 ml). After 5 min., add diisopropylethylamine (DIPEA) (65.2 ml, 0.37mol) and stir at 0° C. for 1 h, cool the reaction mixture to -20° C.,and add 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) as asolid. Stir the reaction vigorously for 4 h at -20° C., add acetic acidas a solution in CH₂ Cl₂ dropwise over 15 min, allow the reaction towarm to 0° C., and add H₂ SO₄ (2N). Stir the reaction an additional 1 h,separate the layers, wash with water, separate and dry the organiclayer. Crystallize the crude product from ethanol/water to obtain thepure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) intoluene (100 ml) at 50° C., add N,O-bis(trimethylsilyl)acetamide (BSA)(7.50 ml, 30.3 mmol). After 0.5 h, add solid TBAF (0.39 g, 1.5 mmol) andstir the reaction at 50° C. for an additional 3 h. Cool the reactionmixture to 22° C., add CH₃ OH (10 ml), wash the reaction mixture withHCl (1N), NaHCO₃ (1N) and NaCl (sat'd.), and dry the organic layer overMgSO₄.

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) inCH₃ OH (3 ml), add water (1 ml) and LiOH-H₂ O (102 mg, 2.4 mmole). Stirthe reaction at 22° C. for 1 h and add additional LiOH-H₂ O (54 mg, 1.3mmole). After a total of 2 h, add HCl (1N) and EtOAc, separate thelayers, dry the organic layer and concentrate in vacuo. To a solution ofthe resultant product (0.91 g, 2.2 mmol) in CH₂ Cl₂ at 22° C., addoxalyl chloride (0.29 ml, 3.3 mmol) and stir for 16 h. Remove thesolvent in VaCUO.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzincchloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M inTHF, 4.4 ml, 4.4 mmol) and ZnCl₂ (0.6 g, 4.4 mmol) at 4° C., addtetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) and theproduct of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). Stirthe reaction for 1 h at 0° C. and then for 0.5 h at 22° C. Add HCl (1N,5 ml) and extract with EtOAc. Concentrate the organic layer to an oiland purify by silica gel chromatography to obtain abs(3R,4S)-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-(3-oxo-3-phenylpropyl)-2-azetidinone:HRMS calc'd for C₂₄ H₁₉ F₂ NO₃ =408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), add(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole(120 mg, 0.43 mmol) and cool the mixture to -20° C. After 5 min, addborohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol)dropwise over 0.5 h. After a total of 1.5 h, add CH₃ OH followed by HCl(1N) and extract the reaction mixture with EtOAc to obtain abs(3R,4S)-4-(4-benzyloxyphenyl)- 1-(4-fluorophenyl)-3-(3(S)-hydroxy-3-(4-fluoro-phenyl)propyl)-2-azetidinone(compound 6A-1) as an oil. ¹ H in CDCl₃ δH3 =4.68. J=2.3 Hz. CI (M+H)500.

Use of(S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone(compound 6B-1). ¹ H in CDCl₃ δH3 =4.69. J =2.3 Hz. CI (M+H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), add10% Pd/C (0.03 g) and stir the reaction under a pressure (60 psi) of H₂gas for 16 h. Filter the reaction mixture and concentrate the solvent toobtain compound 6A. Mp 164-166° C.; CI (M+H) 410. Elemental analysiscalc'd for C₂₄ H₂₁ F₂ NO₃ : C 70.41; H 5.17; N 3.42; found C 70.25; H5.19; N 3.54.

Treat compound 6B-1 in a similar manner to obtain compound 6B. Mp129.5-132.5° C.; CI (M+H) 410. Elemental analysis calc'd for C₂₄ H₂₁ F₂NO₃ : C 70.41; H 5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

Step 6') (Alternative): To a solution of the product of Step 5 (0.14 g,0.3 mmol) in ethanol (2 ml), add 10% Pd/C (0.03 g) and stir the reactionunder a pressure (60 psi) of H₂ gas for 16 h. Filter the reactionmixture and concentrate the solvent to afford a 1:1 mixture of compounds6A and 6B.

Using appropriate starting materials and following the procedure ofsteps 1-6, prepare the following compounds:

    __________________________________________________________________________    6C                                                                               ##STR58##                                                                                                   ##STR59##                                    6D                                                                               ##STR60##                                                                                                   ##STR61##                                    __________________________________________________________________________

EXAMPLE 7 ##STR62##

To a solution of 7a (1.0 g, 2.1 mmol) in dioxane (10 ml), add SeO₂ (1.33g, 11.98 mmol) and water (0.25 ml, 14 mmol), and heat the reaction to100° C. After 1 h, cool the reaction to room temperature and isolate byextraction the crude product as a diastereomeric mixture (1:2) ofalcohols 7b -A and 7b-B. Purify by HPLC on a Dynamax silica column toseparate diastereomers A and B.

Diastereomer A (R): oil; J₃₄ =2.3 Hz, δCH(OH)=4.86 (t)

HRMS C₃₂ H₂₉ NO₄ calc.: 491.2097; found: 491.2074.

Diastereomer B (S): oil; J₃₄ =2.3 Hz, δCH(OH)=5.06 (t)

HRMS C₃₂ H₂₉ NO₄ calc.: 491.2097; found: 491.2117.

Step 2): To a solution of diastereomer A from step 1 (58 mg, 0.12 mmol)in EtOAc (2 ml), add 10% Pd on carbon (20 mg) and stir at 22° C. underH₂ gas (14 psi) for 12 h. Filter and concentrate to obtain the titlecompound as a semisolid, m.p. 90 °-92 ° C. J₃₄ =2.3 Hz, δCH(OH)=4.1 (m);HRMS C₂₅ H₂₅ NO₄ calc.: 403.1783; found: 403.1792.

EXAMPLE 8

To a solution of the product of Example 4A (90 mg, 0.2 mmol) in CH₂ Cl₂,add acetyl chloride (80 mg, 1.0 mmol) and pyridine (8 mg, 0.1 mmol) andstir at room temperature for 1 h. Add water, separate the layers andisolate the corresponding acetoxy compound, 8A. In a similar manner,treat the products of Examples 4B, 6B and 6A to obtain the followingcompounds 8B, 8C and 8D, respectively:

8A: abs (3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3R-acetoxy-3-phenylpropyl)-2-azetidinone.CI (M+H) 460; HRMS C₂₈ H₂₉ NO₅ calc.: 459.2044; found: 459.2045.

8B: abs (3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3S-acetoxy-3-phenylpropyl)-2-azetidinone.CI (M+H) 460; HRMS C₂₈ H₂₉ NO₅ calc.: 459.2044; found: 459.2048.

8C: abs(3R,4S)-4-(4-acetoxyphenyl)-3-(3R-acetoxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone.FAB MS 493.4; HRMS C₂₈ H₂₅ F₂ NO₅ calc.: 493.1695; found: 493.1701.

8D: abs(3R,4S)-4-(4-acetoxyphenyl)-3-(3S-acetoxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone.FAB MS 493.4; HRMS C₂₈ H₂₅ F₂ NO₅ calc.: 493.1695; found: 493.1694.

Using appropriate starting materials in the procedure of Example 6,prepare(3R,4S)-1-(4-chlorophenyl)-3-(hydroxy-3-(4-chlorophenyl)propyl)-4-(4-hydroxyphenyl)-2-azetidinone.Using the procedure of Example 8, prepare the following diacetates 8Eand 8F:

    __________________________________________________________________________    8E                                                                               ##STR63##                                                                                                     ##STR64##                                  8F                                                                               ##STR65##                                                                                                     ##STR66##                                  __________________________________________________________________________

EXAMPLE 9 ##STR67##

Step 1: Add pyridinium chlorochromate (2.4 g, 11 mmoles) and CH₃ CO₂ Na(approx. 20 mg) to a solution of1-phenyl-3-(3-pheny-1-hydroxypropyl)-4-(4-methoxyphenyl)-2-azetidinone(2.35 g, 6.1 mmoles) in CH₂ Cl₂. Stir at room temperatue for 18 h, thenadd silica gel (40 g) and concentrate to dryness. Flash chromatographthe residue using EtOAc:Hex 1:4 to obtain an oil. (1.98 g, yield=85%).H¹ NMR 2.85-2.95 (m, 3H), 3.15 (m, 1H), 3.80 (s, 3H), 4.10 (d, 1H, J2.6), 5.42 (1H, d, J 2.6), 6.85 (dd, 2H, J 2, 8), 7.05 (m, 1H), 7.2-7.35(m, 11H).

Step 2: To a solution of the product of Step 1 (1.78 g, 4.62 mmoles) inTHF at -10° C., add NaH (115 mg ,4.8 mmoles). After 15 min., add NBS(865 mg, 4.85 mmoles) and stir for 20 min., then add 1N HCl andpartition between EtOAc and brine. Separate the organic layer, dry(MgSO₄) and concentrate to give an oil. Flash chromatograph the oilusing EtOAc:Hex (1:10) to collect first 9a as a foamy solid (830 mg,y=39%, FAB MS 466/464, M+H), and then 9b as a colorless solid (1.1 g,y=51%, FAB MS 466/464, M+H).

Step 3a: Add Mg(OCOCF₃)₂ ·CF₃ CO₂ H (7.3 ml of 1M solution in Et₂ 0,) toa solution of 9a (68 g, 1.46 mmoles) in THF (5 ml) at -50° C. Stir thereaction 5 min., then add t-Bu-NH₂ -BH₃ (254 mg, 2.92 mmole). After 15min., allow the reaction to warm to 0° C. over 20 min., add 1N HCl andconcentrate in vacuo. Partition the residue between EtOAc and brine.Concentrate the organic layers and dissolve the resultant oil in CH₂ Cl₂:CH₃ OH (1:1) and add ethanolamine (approx 2 mmoles). After 15 min.,concentrate the reaction mixture and partition the residue with EtOAc:1NHCl. Wash (brine) and dry (MgSO₄) the organic layers to obtain an oil.Purify this oil by flash chromatography using EtOAc:Hex (1:4) to obtaincompound 9a-1, a colorless solid, as a 4:1 mix of diastereomers. 0.52 g,y=76%, SIMS 468/466 (M+H).

Step 3b: Using compound 9b as the starting material, use a proceduresimilar to Step 3a with CH₂ Cl₂ as solvent for the preparation of 9b-1in80% yield as a 13:1 mixture of diastereomers (SIMS 468/466 M+H).

Step 4a: Add a solution of 9a-1 (0.27 g, 0.58 mmoles) and AlBN (18 mg,0.12 mmole) in toluene (40 ml) dropwise over 40 min. to a solution of(TMS)₃ SiH (1.0 ml) in toluene at 80° C. After 1 h, add more AlBN (5 mg)and continue at 80° C. for 1.5 h. Cool and concentrate the reactionmixture, dissolve the residue in CH₃ CN and wash 3× with hexane.Concentrate the CH₃ CN layer to give the title compound as a racemicmixture (0.25g). Purify this oil by HPLC using a Chiralcel OD column toobtain 3H (major) and 3J (minor).

Step 4b: Use the procedure of Step 4a, starting with compound 9b-1 toobtain an oil. Purify this by flash chromatography using EtOAc:Hex 1:3to collect the racemic title compound (y=70%). Purify this oil by HPLCusing a Chiralcel OD column to obtain 3J (major) and 3H (minor).

EXAMPLE 10 ##STR68##

Step 1: Follow the procedure of Example 3, using1-(4-fluorophenyl-4-(4-t-butyldimethylsilyloxyphenyl)-2-azetidinone toobtain 1-(4-fluorophenyl-3-(3-phenyl-1-hydroxypropyl)4-(4-t-butyldimethylsilyl-oxyphenyl)-2-azetidinone.

Step 2: Treat a solution of the cis-azetidinone of Step 1 (0.25 g) inCH₃ CN (21 ml) with 48% aqueous HF (2.5 ml). After 18 h, dilute thereaction mixture with cold H₂ O and extract with Et₂ O. Wash (2× H₂ O,dilute NaHCO₃ and brine), dry (MgSO₄) and concentrate the Et₂ O layer.Crystallize the residue from EtOAc:hexane (1:2) to obtain the titlecompound as colorless needles (123 mg, y=64%), mp 168-171° C.

Elemental analysis calc for C₂₄ H₂₂ O₃ FN: C 73.64; H 5.66; N 3.58.found C 73.32; H 5.65; N 3.68.

The following formulations exemplify some of the dosage forms of thisinvention. In each the term "active compound" designates a compound offormula I.

EXAMPLE A

    ______________________________________                                        Tablets                                                                                                  mg/                                                No.  Ingredient            tablet  mg/tablet                                  ______________________________________                                        1    Active Compound       100     500                                        2    Lactose USP           122     113                                        3    Corn Starch, Food Grade, as a 10%                                                                    30      40                                             paste in Purified Water                                                  4    Corn Starch, Food Grade                                                                              45      40                                        5    Magnesium Stearate     3       7                                              Total                 300     700                                        ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate themixture with Item No. 3. Mill the damp granules through a coarse screen(e.g., 1/4"0.63 cm) if necessary. Dry the damp granules. Screen thedried granules if necessary and mix with Item No. 4 and mix for 10-15minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture toappropriate size and weight on a suitable tablet machine.

EXAMPLE B

    ______________________________________                                        Capsules                                                                      No.   Ingredient       mg/tablet   mg/tablet                                  ______________________________________                                        1     Active Compound  100         500                                        2     Lactose USP      106         123                                        3     Corn Starch, Food Grade                                                                         40          70                                        4     Magnesium Stearate NF                                                                           4           7                                               Total            250         700                                        ______________________________________                                    

Method Of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

Representative formulations comprising a cholesterol biosynthesisinhibitor are well known in the ad. It is contemplated that where thetwo active ingredients are administered as a single composition, thedosage forms disclosed above for substituted azetidinone compounds mayreadily be modified using the knowledge of one skilled in the art. Usingthe test procedures described above, the following in vive data wereobtained for the exemplified compounds. Data is reported as percentchange (i.e., percent reduction in cholesterol esters) versus control,therefore, negative numbers indicate a positive lipid-lowering effect.

    ______________________________________                                        % Reduction                                                                   Ex.     Serum         Cholest. Dose                                           #       Cholest.      Esters   mg/kg                                          ______________________________________                                        1A      -23              0     50                                             1B      -15           -39      50                                             1C      14               0     50                                             2       0                0     50                                             3A      -31           -69      50                                             3C      -60           -92      50                                             3D      -17           -61      10                                             3E      0                0     10                                             3F      -29           -77      10                                             3G      -16           -38      10                                             3H      -41           -86      10                                             3I      0             -22      10                                             3J      0                0     3                                              3K      0                0     10                                             4A      0             -54      5                                              4B      -37           -89      8                                              4C      -12.5            0     3                                              4D      9                0     7                                              4E      0             -46      3                                              4F      -29           -95      3                                              5       0-            -64      10                                             6A      -59           -95      1                                              6B      -40           -92      3                                              6C      0             -48      3                                              6D      -46           -95      10                                             8A      0             -44      3                                              8B      -50           -95      3                                              8C      -14           -37      1                                              8D      -49           -98      1                                              8E      -22           -66      3                                              8F      -43           -94      1                                              10      -26           -77      3                                              ______________________________________                                    

We claim:
 1. A process for preparing a compound of the formula ##STR69##wherein: Ar¹ and Ar² are independently selected from the groupconsisting of aryl and R⁴ -substituted aryl;Ar³ is aryl or R⁵-substituted aryl; X, Y and Z are independently selected from the groupconsisting of --CH₂ --, --CH(lower alkyl)- and --C(dilower alkyl)-; R is--OH, --O(lower alkyl) or --O-- benzyl: R¹ and R³ are independentlyselected from the group consisitng of hydrogen, lower alkyl and aryl; qis 0 or 1; m and n are independently 0, 1, 2, 3 or 4, and p is 0, 1, 2,3 or 4; provided that the sum of m, n, p and q is 1, 2, 3, 4, 5 or 6; R⁴is 1-5 substituents independently selected from the group consisting oflower alkyl, --OH, --O(lower alkyl), --O-benzyl, --NR ⁶ R⁷, --COOR⁶,--CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)₀₋₂ R⁹, -(lower alkylene)COOR⁶,--CH═CH--COOR⁶, --CF₃, --CN, --NO₂ and halogen; R⁵ is is 1-5substituents independently selected from the group consisting of --OH,--O(lower alkyl), --O-benzyl, --NR⁶ R⁷, --COOR⁶, --CONR⁶ R⁷, --COR⁶,--SO₂ NR⁶ R⁷, S(O)₀₋₂ R⁹, -(lower alkylene)-COOR⁶ and --CH═CH--COOR⁶ ;R⁵, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R⁹ islower alkyl, aryl or aryl-substituted lower alkyl, comprising:(a)treating with a strong base in an anhydrous organic solvent a lactone ofthe formula ##STR70## wherein X, Y, Z, R', R³, m, n, p and q are asdefined above, R' is R as defined above or a suitably protected hydroxygroup, and Ar¹⁰ is Ar¹ as defined above, a suitably protectedhydroxy-substituted aryl or a suitably protected amino-substituted aryl;(b) reacting the product of step (a) with an Imine of the formula##STR71## wherein Ar²⁰ is Ar², a suitably protected hydroxy-substitutedaryl or a suitably protected amino-substituted aryl, and Ar³⁰ is Ar³, asuitably protected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl; c) quenching the reaction with an acid; and d)removing as necessary a protecting group from any of substituents R',Ar¹⁰, Ar²⁰ and Ar³⁰ to obtain a compound wherein R, Ar¹, Ar² and Ar³ areas defined above.
 2. The process of claim 1 further comprisingconverting a compound as defined in claim 1 having a hydroxy substituentat R, or a hydroxy or amino substituent at any of Ar¹, Ar² and Ar³, toanother compound of claim 1 wherein a hydroxy at R and at the carbon towhich the R³ substituent is attached is converted to a --OR⁶, --O(CO)R⁶,--O(CO)OR⁹ or --O(CO)NR⁶ R⁷ group: or a hydroxy group at Ar¹, Ar² or Ar³is converted to a --OR⁶, --O(CO)R⁶, --O(CO)OR⁹, --O(CH₂)₁₋₅ OR⁶,--O(CO)NR⁶ R⁷, --O(CH₂)₁₋₁₀ --COOR⁶ or --O(CH₂)₁₋₁₀ CONR⁶ R⁷ group: oran amino group at Ar¹, Ar² or Ar³ is converted to a --NR⁶ R⁷, --NR⁶(CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸ or --NR⁶ SO₂ R⁹ group.
 3. Aprocess for preparing a compound of the formula ##STR72## wherein: Ar¹and Ar² are independently selected from the group consisting of aryl andR⁴ -substituted aryl:Ar³ is aryl or R⁵ -substituted aryl; X, Y and Z areindependently selected from the group consisting of --CH₂ --, --CH(loweralkyl)- and --C(dilower alkyl)-; R² is --OH, --O(lower alkyl) or--O-benzyl: R¹ and R³ are independently selected from the groupconsisitng of hydrogen, lower alkyl and aryl; Pl r is 0 or 1; m, n and pare independently 0, 1, 2, 3 or 4; provided that the sum of m, n. p andr is 1, 2, 3, 4, 5 or 6, and further provided that when r and n are eachzero, p is 1, 2, 3 or 4; R⁴ is 1-5 substituents independently selectedfrom the group consisting of lower alkyl, --OH. --O(lower alkyl),--O-benzyl, --NR⁶ R⁷, --COOR⁶, --CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)₀₋₂R⁹, -(lower alkylene)COOR⁶, --CH═CH--COOR⁶, --CF₃, --CN, --NO₂ andhalogen; R⁵ is is 1-5 substituents independently selected from the groupconsisting of --OH, --O(Iower alkyl), --O-benzyl --NR⁶ R⁷, --COOR⁶,--CONR⁶ R⁷, --COR⁶, --SO₂ NR⁶ R⁷, S(O)₀₋₂ R⁹, -(lower alkylene)-COOR⁶and --CH═CH--COOR⁶ ; R⁶, R⁷ and R⁸ are independently selected from thegroup consisting of hydrogen, lower alkyl, aryl and aryl-substitutedlower alkyl; and R⁹ is lower alkyl, aryl or aryl-substituted loweralkyl, comprising:(a) treating with a strong base in an anhydrousorganic solvent a lactone of the formula ##STR73## wherein X, Y, Z, R¹,R³, m, n, r and p are as defined above, with the further proviso that ifn and r are each zero, p is 1, 2, 3 or 4; Ar¹⁰ is Ar¹ as defined above,a suitably protected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl; and R^(2') is R² as defined above or a suitablyprotected hydroxy group; (b) reacting the product of step (a) with animine of the formula ##STR74## wherein Ar²⁰ is Ar², a suitably protectedhydroxy-substituted aryl or a suitably protected amino-substituted aryl,and Ar³⁰ is Ar³, a suitably protected hydroxy-substituted aryl or asuitably protected amino-substituted aryl; c) quenching the reactionwith an acid; and d) removing as necessary a protecting group from anyof substituents R^(2'), Ar¹⁰, Ar²⁰ and Ar³⁰ to obtain a compound whereinR, Ar¹, Ar² and Ar³ are as defined above.
 4. The process of claim 3further comprising converting a compound as defined in claim 3 having ahydroxy substituent at R², or a hydroxy or amino substituent at any ofAr¹, Ar² and Ar³, to another compound of claim 1 wherein a hydroxy at R²and at the carbon to which the R¹ substituent is attached is convertedto a --OR⁶, --O(CO)R⁶, --O(CO)OR⁹ or --O(CO)NR⁶ R⁷ group; or a hydroxygroup at Ar¹, Ar² or Ar³ is converted to a --OR⁶, --O(CO)R⁶, --O(CO)OR⁹,--O(CH₂)₁₋₅ OR⁶, --O(CO)NR⁶ R⁷, --O(CH₂)₁₋₁₀ --COOR⁶ or--O(CH₂)_(1-10CONR) ⁶ R⁷ group; or an amino group at Ar¹, Ar² Ar³ isconverted to a --NR⁶ R⁷, --NR⁶ (CO)R⁷, --NR⁶ (CO)OR⁹, --NR⁶ (CO)NR⁷ R⁸or --NR⁶ SO₂ R⁹ group.